Asymmetric catalysis using DPEN and proline
derivatives
Charles V. Manvillea, Martin Willsa, Gordon Docherty,b Ranbir Paddab and Gary Woodwoodb.
a: Department of Chemistry, University of Warwick, Coventry, CV4 7AL
b: Rhodia Consumer Specialities Ltd, PO Box 80, Trinity Street, Warley, Oldbury, B69 4LN
Introduction:
Reactions were also run using Rh(Cp*) and Ir(Cp*) as the metal centres. These catalysts gave much lower conversions
and e.e.s for all of the tested ketones, than the corresponding Ru(p-cymene) catalyst.
Amines have been used in catalysts since 1902, when pyridine was used by Dobner in a modification of the
Knoevenagel Condensation.1 The first use of a chiral amine in catalysis was the use of proline in the HaiosParrish-Eder-Sauer-Wiechert reaction in the 1970s.2 Since then proline and it’s derivatives have been used as
organocatalysts in a number of reactions, including conjugate additions to nitrostyrenes,3 Diels-Alder reactions4
and aldol reactions.5 These reactions can be performed with good activity and selectivity with moderate catalyst
loadings.
DPEN is often used as a chiral ligand in metal centred catalysts, most famously in the system reported by Noyori.6
Derivatives of DPEN are used in the Wills group to form tethered catalysts for asymmetric reductions of ketones
and imines where it acts to both impart chirality to the catalyst and act as a hydrogen source in the reduction
step.7
Recently, DPEN derivatives have been investigated for use as organocatalysts.
results has been for the Michael addition of ketones to nitrostyrenes.8,9
One of the more successful
Azo Coupling
It has been shown that derivatives of DPEN and proline, containing a diphenyl phophinamide group, can catalyse
the addition of acetone to nitrostyrenes, but is unsuccessful when using other aldehydes.9
It was attempted to improve the scope of the catalyst by coupling the PODPEN to proline. These catalysts proved
to be unreactive in the Michael addition, but were able to catalyst the coupling of DEAD to aldehydes. Derivatives
using TsDPEN were also made and tested
O
R1
R2
R1
NaCO2H, H2O, 60 °C
Ligand R1
3
4
3
4
3
4
3
4
3
4
3
4
OH
[RhCl2(Cp*)]2, ligand,
R2
Ph
Ph
CHex
CHex
4-MeO phenyl
4-MeO phenyl
4-Cl phenyl
4-Cl phenyl
2-Cl phenyl
2-Cl phenyl
Ph
Ph
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
Et
O
R2
Conv. (%)a e.e.
(%)a
13
84
21
67
22
0
28
0
3
63
7
52
21
83
68
85
41
59
37
50
10
28
7
22
R1
Conf.
R2
R
S
R
S
R
S
R
S
R
S
3
4
3
3
4
R1
NaCO2H, H2O, 60 °C
Ligand R1
b
OH
[IrCl2(Cp*)]2, ligand,
R2
Ph
Ph
4-MeO phenyl
4-Cl phenyl
4-Cl phenyl
Me
Me
Me
Me
Me
R2
Conv. (%)a e.e.
(%)a
9
47
0
5
38
33
29
33
14
Conf.
b
R
R
R
R
a. Determined by G.C. b. Determined by comparison of G.C.
and optical rotation with literature data.
The use of an iridium metal centre changes the major
determination of product chirality from the proline part of
the ligand to the DPEN part of the ligand
a. Determined by G.C. b. Determined by comparison of G.C.
and optical rotation with literature data.
O
Ph
N
H
New catalyst synthesised by coupling proline and a DPEN
derivative. R = Ph2P(O), Ts.
HN
Ph
Further ligands were synthesised by coupling two Boc-(S)-prolines to a central DPEN unit, using the same conditions as
for the coupling of Boc-(S)-proline to TsDPEN.
HN
R
O
O Ph
HN P
Ph
Ph
H2N
Ph
Boc
a
N
64%
O
O Ph
NH HN P
Ph
Ph
Ph
O Ph
NH HN P
Ph
Ph
Ph
b
HN
46%
O
a
49%
Boc
N
O
O Ph
NH HN P
Ph
Ph
Ph
b
HN
9%
a
HN Ts
NH HN Ts
N
Ph
Ph
NH2
Ph
a
79%
Ph
Ph
HN
72%
Ph
NH
Ph
a
NH HN Ts
Ph
Ph
HN
50%
Ph
Ph
O
R1
O
R
N
OEt
N
OEt
HN
N
CO2Et
Ligand
CO2Et
R
O
O
O
HN
OEt
N
OEt
O
O
0%
HN
OEt
N
OEt
O
3 1 hr
e.e. = 93% (R)
4 45 min e.e. = 87% (R)
3 24 hr
4 6 hr
e.e. = 81% (R)
e.e. = 74% (R)
e.e. = 85% (R)
e.e. = 52% (R)
Asymmetric Transfer Hydrogenation
Derivatives of both DPEN6,7 and proline10 have been used as ligands for the asymmetric transfer hydrogenation of
ketones using metal centres. The Ts-DPEN derivatives were tested as ligands, and were found to be successful
when used with a ruthenium p-cymene metal centre in water, using sodium formate as the hydrogen donor, at a
catalyst loading of 1 mol%.
NaCO2H, H2O, 60 °C
O
OH
[RuCl2(p-cymene)]2, ligand,
R1
N
N
Ph
NH HN
b
HN
57%
Ph
NH
Ph
Ph
OH
[RuCl2(p-cymene)]2, ligand,
R2
NaCO2H, H2O, 60 °C
R1
OH
[RuCl2(p-cymene)]2, ligand,
5
6
5c
6c
5
6
5
6
5
6
5
6
5
6
5
6
5
6
6
R1
Ph
Ph
Ph
Ph
CHex
CHex
4-MeO phenyl
4-MeO phenyl
2-MeO phenyl
2-MeO phenyl
4-Cl phenyl
4-Cl phenyl
2-Cl phenyl
2-Cl phenyl
Ph
Ph
Ph
Ph
Ph
R2
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
Et
CHex
CHex
CH2C
l
Conv. (%)a
99
100
11
13
54
22
63
90
66
98
100
98
99
99
82
90
82
90
100
e.e.
(%)a
86
83
12
24
68
66
83
77
65
53
87
79
80
66
86
80
86
80
81
OH
O
[RuCl2(p-cymene)]2, ligand,
R
n
R2
Conf.
Ligand
X R
n Conv. (%)a
b
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
Catalyst loading; 1 mol%. a. Determined by G.C. b. Determined by
comparison of G.C. and optical rotation with literature data. c.
[RhCl2(Cp*)]2 used instead of [RuCl2(p-cymene)]2
5
6
6d
5
6
6
6
6
6
6
6
6
C
C
C
C
C
C
C
C
C
O
O
S
R
n
NaCO2H, H2O, 60 °C
X
CO2Et
O
HN
1 48 hr
2 No
Reaction
3 48 hr
4 4 hr
O
Cat. (5 mol%)
O
O
Boc
When these new ligands were tested, using the same conditions used for ligands 3 and 4, in the transfer hydrogenation
of ketones, they proved to be faster than the TsDPEN ligands, but had a lower selectivity for linear ketones. However,
the hydrogenation of cyclic indanone and tetralone like ketones gave good to high e.e.s in all of the tested ketones when
using ligand 6.
Ph
a: N-Boc-(S)-proline, ethyl chloroformate, Et3N, THF.
b: 20%Me2S-DCM, triisopropylsilane, TFA, 0 °C.
c: Formic acid, 0 °C
N
NH HN
Boc
O
a: N-Boc-(S)-proline, ethyl chloroformate, Et3N, THF.
b: 20%Me2S-DCM, triisopropylsilane, TFA, 0 °C.
Ph
4
+
O
NH HN Ts
c
N
CO2Et
O
O
Boc
44%
Ph
Ph
6
3
HN Ts
R2
N
5
HN
78%
(S,S)
R1
N
NH HN
b
NH HN Ts
b
O
O
Boc
O
(S,S)
(R,R)
Ph
O
NH HN
Boc
79%
Ph
H2N
O
Boc
86%
Ph
H2N
a
O
2
O
Ph
Ph
O Ph
NH HN P
Ph
Ph
Ph
(S,S)
H2N
NH2
O
(R,R)
O Ph
HN P
Ph
Ph
Ph
H2N
1
(R,R)
H2N
O
H
H
H
H
H
H
7-Me
6-OMe
Furan
H
6-Cl
H
2
2
2
1
1
3
1
2
2
2
2
2
14
48
98
99
100
61
43
13
11
100
X
e.e.
(%)b
75
98
96
71
91
89
89
85
85e
96e
86
92
Conf.
c
R
R
R
R
R
R
R
R
R
R
R
R
Catalyst loading; 1 mol%.
a. Determined by G.C. b.
Determined by G.C. unless shown. c. Determined by
comparison of G.C. and optical rotation with literature data. d.
2 mol% catalyst used. e. Determined by HPLC
For the cyclic ketones the ligand formed from the
coupling of two (S)-prolines to (S,S)-DPEN (6)
proves to form a faster and more selective catalyst
for all of the tested substrates than the (S)-proline /
(R,R)-DPEN ligand (5).
NaCO2H, H2O, 60 °C
R2
Acknowledgements:
Ligand R1
3
4
3
4
3
4
3
4
3
4
3
4
3
4
3
4
Ph
Ph
CHex
CHex
4-MeO phenyl
4-MeO phenyl
2-MeO phenyl
2-MeO phenyl
4-Cl phenyl
4-Cl phenyl
2-Cl phenyl
2-Cl phenyl
Ph
Ph
Ph
Ph
R2
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
Et
CHex
CHex
Conv. (%)a
100
100
25
40
76
92
54
95
90
100
100
100
66
84
6
6
e.e.
(%)a
90
83
0
0
86
57
74
65
88
71
85
64
84
78
32
57
Conf.
b
R
R
R
R
R
R
R
R
R
R
R
R
R
R
Catalyst loading; 1 mol%. a. Determined by G.C. b. Determined by
comparison of G.C. and optical rotation with literature data.
Ligand
3
4
Conv. (%)a
8
45
e.e. (%)a
77
78
Conf.b
R
R
Catalyst loading; 1 mol%. a. Determined by G.C. b.
Determined by comparison of G.C. and optical rotation with
literature data.
I would like to thank Martin and the Wills group for their support and encouragement during this project. I would
also like to thank my industrial supervisors Gary Woodwood and Gordon Docherty and the EPSRC and Rhodia for
financial support.
References:
1 O. Doebner. Berichte der deutschen chemischen Gesellschaft, 1902, 35, 1136-1147
2 Z. G. Hajos, D. R. Parrish. J. Org. Chem. 1974, 39, 1615-1621; U. Eder, G. Sauer and R. Wiechert, Angew. Chem. Int. Ed.
1971, 10, 496-497.
These results show that for a ruthenium centre the
selectivity of the catalysts is mainly determined by
the proline portion of the ligand, with the most
selective catalyst being the one using (S)-proline
coupled to (R,R)-TsDPEN as the ligand (3). The (S)proline / (S,S)-TsDPEN ligand (4) forms a faster
catalyst in most cases
3 B. List, P. Pojarliev and H. J. Martin. Org. Lett. 2001, 3, 2423; J.M. Betancort, K. Sakthivel, R. Thayumanavan, C.F. Barbas III.
Tetrahedron Lett. 2001,42, 4441
4 H. Sundén, R. Rios, Y. Xu, L. Eriksson and A. Córdova. Adv. Synth. Catal. 2007, 349, 2549-2555
5 Q. Gu, X-F. Wang, L. Wang, X-Y. Wu and Q-L. Zhou. Tetrahedron Asymmetry, 2006, 17, 1537-1540
6 H. Doucet, T. Ohkuma, K. Murata, T. Yokozawa, M. Kozawa, F. Katayama, A.F. England, T.
Chem. Int. Ed. 1998, 37, 1703-1707
Ikariya and R. Noyori. Angew.
7 For recent work see: J.E.D. Martins, G.J. Clarkson and M. Wills, Org Lett, 2009, 11, 847-850; J.E.D. Martins, D.J. Morris and M.
Wills, Tetrahedron Lett. 2009, 50, 688-692
8 S. B. Tsogeova and S. Wei, Chem. Commun. 2006, 1451-53
9 D. J. Morris, A. S. Partridge, C. V. Manville, D.T. Racys, G. Woodward, G. Docherty and M. Wills, Tetrahedron Lett. 2010, 51,
209-212
10 For recent work see: Z. Zhou, L. Wu, Catalysis Communications, 2008, 9, 2539-2542; J. Mao and J. Guo, Chirality, 2010, 22,
173-181